Abstract: Project #3 Rapid delivery to the brain enhances the abuse potential of drugs of abuse, including nicotine. As proposed by Shihadeh and Eissenberg, ?nicotine flux?, or the rate at which a given electronic cigarette (e-cigarette) delivers nicotine, is the most critical factor for evaluating its abuse potential. In this model, when an e-cigarette delivers nicotine at rates above a certain, yet undetermined, threshold it can have high abuse potential and may initiate or maintain tobacco addiction. In contrast, when the nicotine flux is optimal, that e-cigarette may have low addiction potential while providing sufficient nicotine delivery to help smokers quit smoking by alleviating urges to smoke. This proposed ?optimal nicotine flux? concept has yet to be empirically assessed in controlled human studies. In addition, flavors and other e-cigarettes ingredients may also affect the impact of delivery rate on the addictive effects of nicotine. Most notably, menthol may have such an effect through inhibition of nicotinic receptors and slowing of nicotine metabolism. Systematic studies from our group and others have shown that intravenous (IV) nicotine infusion is an optimal approach for quantifying the influence of delivery rate on nicotine's behavioral and physiological effects. The primary aim of this project is to examine the impact of nicotine delivery rate on nicotine's abuse potential (assessed by positive subjective effects and reinforcement), and its potentially beneficial effects of alleviating smoking urges and withdrawal. We also seek to determine if switching from menthol to non-menthol cigarettes, modeling a ban on menthol cigarettes, changes the impact of nicotine delivery rate on the study outcomes. To reach these goals, we propose 2 placebo-controlled studies that will recruit male and female nicotine dependent smokers. Study 1 will recruit equal numbers of menthol (n=35) and non-menthol (n=35) preferring smokers for 5 experimental sessions, which will be at least 24 hours apart. Each session will include 1 randomly assigned infusion that will be either saline or a single dose of nicotine (1 mg per 70 kg body weight) delivered at 4 different infusion rates: 0.24, 0.096, 0.048 or 0.024 g per kg body weight per second). The rates are within the range of nicotine delivery rates achieved by combustible and e-cigarettes and have been piloted in our recent study. In Study 2, menthol- preferring smokers (n=38) will be randomized to a sequence of menthol or non-menthol cigarette smoking conditions, each lasting for 2 weeks, using a crossover design. During week 2 of each period, 3 experimental sessions will be held on 3 separate days. The results from our application will help the FDA in establishing standards for nicotine delivery rates that minimize the addictive risks of e-cigarettes and other electronic nicotine delivery systems (ENDS).